YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

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De Franco , E , Lytrivi , M , Ibrahim , H , Montaser , H , Wakeling , M N , Fantuzzi , F , Patel , K , Demarez , C , Cai , Y , Igoillo-Esteve , M , Cosentino , C , Lithovius , V , Vihinen , H , Jokitalo , E , Laver , T W , Johnson , M B , Sawatani , T , Shakeri , H , Pachera , N , Haliloglu , B , Ozbek , M N , Unal , E , Yildirim , R , Godbole , T , Yildiz , M , Aydin , B , Bilheu , A , Suzuki , I , Flanagan , S E , Vanderhaeghen , P , Senee , V , Julier , C , Marchetti , P , Eizirik , D L , Ellard , S , Saarimäki-Vire , J , Otonkoski , T , Cnop , M & Hattersley , A T 2020 , ' YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress ' , Journal of Clinical Investigation , vol. 130 , no. 12 , pp. 6338-6353 . https://doi.org/10.1172/JCI141455

Title: YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
Author: De Franco, Elisa; Lytrivi, Maria; Ibrahim, Hazem; Montaser, Hossam; Wakeling, Matthew N.; Fantuzzi, Federica; Patel, Kashyap; Demarez, Celine; Cai, Ying; Igoillo-Esteve, Mariana; Cosentino, Cristina; Lithovius, Väinö; Vihinen, Helena; Jokitalo, Eija; Laver, Thomas W.; Johnson, Matthew B.; Sawatani, Toshiaki; Shakeri, Hadis; Pachera, Nathalie; Haliloglu, Belma; Ozbek, Mehmet Nuri; Unal, Edip; Yildirim, Ruken; Godbole, Tushar; Yildiz, Melek; Aydin, Banu; Bilheu, Angeline; Suzuki, Ikuo; Flanagan, Sarah E.; Vanderhaeghen, Pierre; Senee, Valerie; Julier, Cecile; Marchetti, Piero; Eizirik, Decio L.; Ellard, Sian; Saarimäki-Vire, Jonna; Otonkoski, Timo; Cnop, Miriam; Hattersley, Andrew T.
Contributor: University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Institute of Biotechnology
University of Helsinki, Electron Microscopy
University of Helsinki, Centre of Excellence in Stem Cell Metabolism
University of Helsinki, Helsinki One Health (HOH)
Date: 2020-12-01
Language: eng
Number of pages: 16
Belongs to series: Journal of Clinical Investigation
ISSN: 0021-9738
URI: http://hdl.handle.net/10138/324513
Abstract: Neonatal diabetes is caused by single gene mutations reducing pancreatic pcell number or impairing beta cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in beta cells. We identified 6 patients from 5 families with homozygous mutations in the MPS gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human beta cell models (YIPF5 silencing in EndoC-beta H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects beta cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and beta cell failure. Partial YIPF5 silencing in EndoC-beta H1 cells and a patient mutation in stem cells increased the beta cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in beta cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
Subject: PROTEIN RESPONSE CONTRIBUTES
PANCREATIC BETA-CELLS
CORTICAL NEUROGENESIS
TRANSCRIPTION FACTOR
GOLGI STRESS
ER STRESS
GENERATION
EXPRESSION
APOPTOSIS
PUMA
3123 Gynaecology and paediatrics
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